The synthesis of large rings is a challenging problem of the synthetic organic chemistry. On the con โ Organic Chemistry Chemistry Question
Synthesis of large rings. The magic or routine work ?
The synthesis of large rings is a challenging problem of the synthetic organic chemistry. On the contrary, Nature solves this problem efficiently. Thus, various fungus produce macrolactone polyketides. One of them, Macrosphelide A, attracts attention as potent, orally bioavailable inhibitor of the interaction between cancer and endothelial cells. A number of syntheses of this molecule was reported. One of them was based on the utilization of lactic (2-hydroxypropionic) acid derivative according to Scheme below.
[VISUAL]
Decipher this scheme. Write down the structural formulae of compounds A - L.
Model Answer
Based on the provided solution, the compounds are deciphered as follows:
- A: The Weinreb amide of PMB-protected lactic acid, prepared via a mixed anhydride from 2-(p-methoxybenzyloxy)propionic acid and Me3CCOCl, followed by treatment with MeNHOMe. Structure: (S-2-(4-methoxybenzyloxy-N-methoxy-N-methylpropanamide [1, 2].
- B: Ortho-ester of protected 5-hydroxy-4-oxohex-2-enoic acid, formed by the condensation of alkenyllithium (generated from the alkenyl iodide ortho-ester with t-BuLi) with Weinreb amide A [1-3].
- C: The secondary alcohol obtained by the reduction of ketone B with LiBEt3H [1, 3].
- D: The MEM-protected derivative of C, formed by alkylation with methoxyethoxymethyl chloride [1, 3].
- E: (E,4R,5S-5-(4-methoxybenzyloxy-4-(2-methoxyethoxymethoxy)hex-2-enoic acid, obtained via hydrolysis of the ortho-ester group of D [1, 3, 4].
- F: The allyl ester of acid E, prepared by alkylation of E with allyl bromide [1, 5].
- G: The hydroxy ester formed by removing the PMB (4-methoxybenzyl) protecting group of F using DDQ [1, 5].
- H: The ester formed by coupling G (free OH group) and E (free CO2H group) using DCC and DMAP [1, 6, 7].
- I: The alcohol formed by removing the PMB protecting group from H using DDQ [1, 7].
- J: The ester formed by coupling alcohol I with 3-(p-methoxybenzyloxy)butyric acid using DCC and DMAP [1, 7].
- K: The carboxylic acid formed by deprotection of J, involving removal of both the PMB protecting group (with DDQ) and the allyl group (with Pd(PPh3)4) [1, 8].
- L: The free hydroxy acid formed by the removal of the methoxyethoxymethyl (MEM) protecting groups from K using CF3CO2H, which subsequently undergoes Yamaguchi reagent-induced cyclization to yield Macrosphelide A [1, 4].
Write down the IUPAC name of compound E.
Model Answer
(ะ,4R,5S-5-(4-methoxybenzyloxy-4-(2-methoxyethoxymethoxy)hex-2-enoic acid [4].